Aging and age related co-morbidities are major risk factors for neurological pathologies. As the population ages, this puts a major strain on public health. One population that is particularly at risk in the United States are human immunodeficiency virus-1 (HIV-1) infected individuals as more than half of the population is now 50 years of age or older. Infected individuals show signs of premature aging and are prone to neurological dysfunctions collectively known as HIV-associated neurocognitive disorders (HAND). The persistence of HAND has been troubling since with the advent of highly active antiretroviral therapy (HAART), the virus is sufficiently suppressed. Possible contributors to HAND therefore include the HAART drugs themselves as well as reservoirs of the gp120 viral envelope protein hidden in the CNS. Since advancing age is critical for HAND, it is likely that there is an interaction between aging and the factors that influence HAND pathology. We propose that an age associated stress response in astrocytes known as cellular senescence in response to HAART drugs and gp120 could be a contributor to HAND. We will examine the senescence-associated DNA damage response, telomere damage and oxidative stress pathways activated in response to these stimuli. Since senescence is accompanied by the secretion of pro-inflammatory proteins known as the senescence- associated secretory phenotype, we will also determine the contribution of senescent astrocytes to inflammation in response to these HIV-associated stimuli. We will also determine which signaling mechanisms contribute to the secretions by using pharmacological inhibitors of major inflammatory centers. Neurons are also sensitive to glial activation and their toxicity in response to activated glia are another possible HAND contributor. We will examine if secretions from HIV-associated senescent astrocyte are able to cause neurotoxicity and whether pharmacological inhibition of inflammation can mitigate this response. Our overall objective is to determine the interaction between aging and HIV-associated factors as a contributor to HAND. Since many age associated pathologies are associated with the accumulation of senescent cells, astrocyte senescence in response to HAART drugs and gp120 could be a major contributor to HAND and Inhibition of this response could be a public health boon as a potential therapy.
Although highly active antiretroviral therapy (HAART) has been successful in decreasing HIV infection and increasing the average lifespan of the HIV-infected population, patients age prematurely and suffer from age- related neurological pathologies. This proposal investigates astrocyte senescence and dysfunction as a contributor to neuroAIDS. Determining the contribution of senescent astrocytes to neuroAIDS is a major issue to public health as inhibitors provide therapeutic potential to patients.
|Cohen, Justin; Torres, Claudio (2017) HIV-associated cellular senescence: A contributor to accelerated aging. Ageing Res Rev 36:117-124|
|Cohen, Justin; D'Agostino, Luca; Wilson, Joel et al. (2017) Astrocyte Senescence and Metabolic Changes in Response to HIV Antiretroviral Therapy Drugs. Front Aging Neurosci 9:281|